Thioamides, preparation

When chloroacetaldehyde is condensed with higher thioamides prepared from amides and phosphorus pentasulfide according to Schwarz s method (222), 2-substituted thiazoles are obtained (4, 10,"22, 175). 

Amino acid dithioesters have been used as building blocks for the synthesis of en-dothiopeptides, the dithioesters will condense with a-amino groups of N-unprotected amino acids to form thioamides. Preparation of optically active amino acid dithioesters and subsequent formation of thioamide bonds without racemization are two problems that need to be addressed when using this approach to prepare endothiopeptides. The Pinner reaction (Section 15.1.11.1) 1 and Lawesson s procedure (Section 15.1.11.2)M have been successfully used to prepare optically active amino acid dithioesters a modification of Lawesson s procedure via thioamides is also successful.[81... 

Thioamides are used as more reactive precursors than amides for amidine synthesis. Lawesson reagent is normally used for conversion of amide to thioamide. Preparation of an amidine-type mannosidase inhibitor 6 is shown as a representative example [14] (Scheme 3.13). 

Apart from thioamide preparations already alluded to, conditions for the synthesis of aliphatic thioamides, monothiooxamides, dithioamides, and a-ketocarboxylic acid thioamides were described,along with those for the aminosulphuration of capto-... 

This preparation illustrates the ready formation of the thiazole ring by the condensation of an ot-halogeno-ketone and a thioamide. Thus chloroacetone, which may conveniently be represented in the enol form (I), condenses with thiourea (II) to give 2-amino-4-methylthiazolc (III). 

The preparation of these [4-hydroxy-THISs, (1), X = O] by cydization of a-carboxy-N-arylthiobenzimides (5) by treatment with acetic anhydride and triethylamine has been investigated in detail, and the structure has been revised for the compound previously described as 2.3-diphenyl-4-hydroxythiazolium hydroxide inner salt (1, X = 0, R = R = Ph, R = H) (Scheme 5) (3, 10). 4-Hydroxy-THlSs also arise by condensation of gem-dicyanoepoxides with thioamides (Scheme 6) (8). 

The O-S exchange method in presence of a-halogenated carbonyl compound is a very good one for thiazole compounds. The thioamide is prepared in situ by the action of amide upon phosphorus pentasulphide with solvent. The a-halogenated aldehyde reacts directly. But the O-Se exchange cannot be performed with a-halogenated carbonyl compounds because of the apparition of phosphoric acid. (Scheme 3), The C-Se bond is very sensitive to add pH. 

Aromatic thioamides can be prepared as described in the literature by different ways, either by S -> O exchange between the corresponding benzamides and phosphorus pentasulfide in pyridine solution in the presence of triethylamine (65, 646) as strong base, or by action of H2S on the appropriate nitrile with pyridine and triethylamine solvents using the method of Fairfull et al. (34, 374, 503). In this reaction, thioacetamide in acidic medium can also be used as a H2S generator with dimethylform-amide as the solvent (485). 

Owing to the instability of a-halogenoaldehydes it is occasionally preferable to use more stable derivatives, such as enol acetate prepared according to Bedoukian s method (204) and a-bromoacetals (4, 8, 10, 16, 22, 67, 101, 426). An advantage is said to be in the yield however, this appears to be slight. The derivatives react in the same sense as the aldehydes themselves, that is, the acetal group as the more polarized reacts first and enters the C-4 position. It is likely that the condensation and cyclization occur by direct displacement of alkoxide ions. Ethyl-a,/3-dihalogeno ethers (159, 164, 177, 248) have also been used in place of the free aldehydes in condensation with thioamides. 

Dimethylaminoethylthiazoles (17) were prepared from thioamides and l-bromo-4-dimethylamino-2-butanone (16), with R, =Me, CH2Ph, (CH2)NHCOPh, and (Ac)2NCH2 (Scheme 9) (337, 392). 

A series of meta- and para-bis (2-thiazolyI) benzenes and of meta- and para-bis(4-thiazolyl)benzenes of general formula 35 and 36 was prepared in higher yields (60-90%) from the appropriate bis-(haloacetyl)benzenes with a suitable thioamide (Scheme 18a and Table JI-8) (573, 574),... 

Benzocycloheptathiazoles (60) were prepared by the reaction of 6-bromo-l-benzosuberone (59) with the corresponding thioamides, by refluxing for 4 hr in alcoholic solution (Scheme 27) with R = Me, yield is 35%. 

Ethyl-4,5-thiazole dicarboxylates (77), R =H, Me, Et, Ph, or heteroaryl, were prepared from diethyl-a-chloro-/3-ketosuccinate (76) and thioamides in boiling ethanol (Scheme 35) (103, 110, 145, 298, 577, 639). 

Thiazole acetic acids and their hotnologs can also be prepared by cyclization procedures 4-thiazole alkanoic acids and their salts were prepared by treating a thioamide with a -y-chloro- or 7-bromoacetoacetic or their a-alkyl derivatives (4, 10, 16, 22, 273, 275, 281, 640, 647, 695). 

Thiazolium salts with alkyl (103, 722), arylalkyl (116), aryl (305), or heteroaryl (96) substituents on the nitrogen have been also prepared by this procedure. As in the thiazole series, N-substituted thioamides can be formed directly in the reaction mixture from phosphorus pentasulfide and N-substituted amides (127). These methods are important in the synthesis of thiamine 102 (vitamin Bj) (Scheme 45). 

CONHj, COjEt, were also prepared by ring closure of thioamides such as RiCONHCH(R2)C(=S)NH2 with polyphosphoric acid (2 hr at 120°C) (718). 

The most widely used method for the preparation of carboxylic acids is ester hydrolysis. The esters are generally prepared by heterocyclization (cf. Chapter II), the most useful and versatile of which is the Hantzsch s synthesis, that is the condensation of an halogenated a- or /3 keto ester with a thioamide (1-20). For example ethyl 4-thiazole carboxylate (3) was prepared by Jones et al. from ethyl a-bromoacetoacetate (1) and thioformamide (2) (1). Hydrolysis of the ester with potassium hydroxide gave the corresponding acid (4) after acidification (Scheme 1). 

In catalytic hydrogenation, a compound is reduced with molecular hydrogen in the presence of a catalyst. This reaction has found appHcations in many areas of chemistry including the preparation of amines. Nitro, nitroso, hydroxylamino, azoxy, azo, and hydrazo compounds can all be reduced to amines by catalytic hydrogenation under the right conditions. Nitriles, amides, thioamides, and oximes can also be hydrogenated to give amines (1). Some examples of these reactions foUow ... 

Cyanopyridazines add ammonia, primary and secondary amines and hydroxylamine to give amidines or amidoximes. Substituted amides, thioamides and carboximidates can be also prepared. With hydrazine, 3-pyridazinylcarbohydrazide imide is formed and addition of methylmagnesium iodide with subsequent hydrolysis of the imine affords the corresponding pyridazinyl methyl ketone. 

Thiazolines and thiazolidines may also be prepared in this fashion, the structure of the final product determining the substitution pattern to be chosen in the reaction components. Reaction of ethyl bromoacetate with the substituted thioamide (71) resulted in formation of the thiazolidin-4-one (72) (70KGS1621). 

The thiophene analog of chloramphenicol (255) has been synthesized,as also have been similar structures. The antibacterial activity of all was much lower than that of the natural antibiotic. The thioamide of 2-thenoic acid has been prepared in a study of potential antitubercular compounds. It did not surpass thioisonico-tinamide in antitubercular activity. The thiosemicarbazones of thio-phenealdehydes and ketones (cf. Section VII,D) show high activity against Mycobacterium tuberculosis, but are very toxic. The thiosemi-carbazone of 4-(2-thienyl)-3-buten-2-one has been reported to be capable of completely inhibiting the in vitro growth of M. tuberculosis even in relatively low concentrations. ... 

A thioamide of isonicotinic acid has also shown tuberculostatic activity in the clinic. The additional substitution on the pyridine ring precludes its preparation from simple starting materials. Reaction of ethyl methyl ketone with ethyl oxalate leads to the ester-diketone, 12 (shown as its enol). Condensation of this with cyanoacetamide gives the substituted pyridone, 13, which contains both the ethyl and carboxyl groups in the desired position. The nitrile group is then excised by means of decarboxylative hydrolysis. Treatment of the pyridone (14) with phosphorus oxychloride converts that compound (after exposure to ethanol to take the acid chloride to the ester) to the chloro-pyridine, 15. The halogen is then removed by catalytic reduction (16). The ester at the 4 position is converted to the desired functionality by successive conversion to the amide (17), dehydration to the nitrile (18), and finally addition of hydrogen sulfide. There is thus obtained ethionamide (19)... 

Although the antithyroid activity of compounds incorporating an enolizable thioamide function was discussed earlier, this activity was in fact first found in the pyrimidine series. The simplest compound to show this activity, methylthiouracil (80) (shown in both enol and keto forms), is prepared quite simply by condensation of ethyl acetoacetate with thiourea.Further work in this series shows that better activity was obtained by incorporation of a lipophilic side chain. Preparation of the required dicarbonyl compound starts with acylation of the magnesium enolate of the unsyrametrically esterified malonate, 81, with butyryl chlo-... 

N-Substituted amides can be prepared by direct attack of isocyanates on aromatic rings.The R group may be alkyl or aryl, but if the latter, dimers and trimers are also obtained. Isothiocyanates similarly give thioamides. The reaction has been carried out intramolecularly both with aralkyl isothiocyanates and acyl isothiocyanates.In the latter case, the product is easily hydrolyzable to a dicarboxylic acid this is a way of putting a carboxyl group on a ring ortho to one already there (34 is... 

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